Author Identifier
John Olynyk Orcid: https://orcid.org/0000-0003-0417-3411
Document Type
Journal Article
Publication Title
Scientific Reports
ISSN
2045-2322
Volume
9
Issue
1
First Page
8541
Last Page
8541
PubMed ID
31189969
Publisher
Nature Publishing Group
School
School of Medical and Health Sciences
RAS ID
28838
Funders
Funding information available at: https://doi.org/10.1038/s41598-019-44865-1
Grant Number
NHMRC Number : 1048740
Abstract
During chronic liver injury hepatic stellate cells (HSCs), the principal source of extracellular matrix in the fibrotic liver, transdifferentiate into pro-fibrotic myofibroblast-like cells - a process potentially regulated by microRNAs (miRNAs). Recently, we found serum miRNA-25-3p (miR-25) levels were upregulated in children with Cystic Fibrosis (CF) without liver disease, compared to children with CF-associated liver disease and healthy individuals. Here we examine the role of miR-25 in HSC biology. MiR-25 was detected in the human HSC cell line LX-2 and in primary murine HSCs, and increased with culture-induced activation. Transient overexpression of miR-25 inhibited TGF-β and its type 1 receptor (TGFBR1) mRNA expression, TGF-β-induced Smad2 phosphorylation and subsequent collagen1α1 induction in LX-2 cells. Pull-down experiments with biotinylated miR-25 revealed Notch signaling (co-)activators ADAM-17 and FKBP14 as miR-25 targets in HSCs. NanoString analysis confirmed miR-25 regulation of Notch- and Wnt-signaling pathways. Expression of Notch signaling pathway components and endogenous Notch1 signaling was downregulated in miR-25 overexpressing LX-2 cells, as were components of Wnt signaling such as Wnt5a. We propose that miR-25 acts as a negative feedback anti-fibrotic control during HSC activation by reducing the reactivity of HSCs to TGF-β-induced collagen expression and modulating the cross-talk between Notch, Wnt and TGF-β signaling.
DOI
10.1038/s41598-019-44865-1
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Research Themes
Health
Priority Areas
Prevention, detection and management of cancer and other chronic diseases
Comments
Genz, B., Coleman, M. A., Irvine, K. M., Kutasovic, J. R., Miranda, M., Gratte, F. D., ... Ramm, G. A. (2019). Overexpression of miRNA-25-3p inhibits Notch1 signaling and TGF-β-induced collagen expression in hepatic stellate cells. Scientific Reports, 9(1), Article 8541. Available here